DECLARATION OF CONFLICT OF INTEREST

DECLARATION OF CONFLICT OF INTEREST

Disclosures: Research grants & clinical trials (Gilead), honoraria & clinical trials (Berlin-Chemie/Menarini) Ranolazine in Heart Failure with Preserved Ejection Fraction (HFpEF) Lars S. Maier Dept. of Cardiology and Pneumology, Heart Center, Göttingen, Germany

Pieske et al. et al., Circulation, 2002 [Na] i is associated with diastolic dysfunction human:

I Na in heart failure human: Peak I Na Late I Na Ranolazine (~40-fold selectivity of late I Na vs. peak I Na ) Effects on diastolic function? Belardinelli et al., Europ Heart J Suppl, 2004 Maltsev et al., Circulation, 1998, CMLS, 2002 Valdivia et al., JMCC, 2005

Isolated human muscle strips

human: Improved diastolic function through late I Na inhibition with ranolazine Heart Failure Ranolazine 3 Hz 0.5 Hz 0.5 Hz 3 Hz Severe diastolic dysfunction improved diastolic function 500 ms Sys0.5/3Hz Diastolic tension (mn/mm 2 ) 18 16 14 12 10 8 6 4 2 Vehicle Ran p<0.05 0 0 1 2 3 41 * Frequency (Hz) Developed tension (mn/mm 2 ) 10.0 7.5 5.0 2.5 0.0 Vehicle Ran 0.5 3.0 Frequency (Hz) Sossalla et al., JMCC, 2008

Decreased late I Na by ranolazine rabbit: 50 ms Vehicle 0 0 Late I Na Integral (A*F -1 *ms) -200-400 Vehicle 1 A/F ATX-II+Ran ATX-II 5 ms 50 mv 1000 ms -20 mv -140 mv 50 ms 500 ms Ran P<0.05 ATX-II ATX-II+ Ran Peak I Na (A*F -1 ) -20-40 -60-80 Vehicle Ran ATX-II ATX-II+ Ran P<0.05 P<0.05 ATX-II 40 nmol/l Sossalla et al., JMCC, 2008

Late I Na inhibition delays contracture in atria human: 2.5 µmol/l Ouabain 10 mn/mm 2 10 mn/mm 2 Vehicle 30 min Ran 30 min Normal Time to contracture (min) 125 100 75 50 25 0 * Vehicle N=5/4 N=6/4 *Ran Ischemia, Heart failure, H 2 O 2 Sossalla et al., JACC, 2010 20 pa/pf I Na,late I Na,late peak I Na peak I Na How may late I Na be activated?

CaMKII associates with & regulates cardiac Na channels mouse: rabbit: Co-Immunostaining Late I Na CaMKII Na V 1.5 1 Merge 50 ms Gal CaMKII C +KN93 2 0.01 CaMKII C 1 2 3 1000 ms -20 mv 3 50 ms -140 mv 500 ms 10 µm 10 µm 10 µm Wagner et al., JCI, 2006 Hund et al., JCI, 2010

mouse: Impaired systolic and diastolic contractility in TG CaMKII C in vivo WT TG ESD EDD ESD EDD Fractional area shortening (%) 60 50 40 30 20 10 0 WT (n=5) * TG (n=5) Ejection fraction (%) 60 50 40 30 20 10 0 WT (n=5) * TG (n=5) Relaxation velocity (cm/s) -0.5-1.0-1.5-2.0-2.5 WT (n=5) TG (n=5) * Sossalla et al., Basic Res Cardiol, 2011

Late I Na inhibition in CaMKII TG mice improves diastolic tension in heart failure mouse: WT TG 1 mn/mm² 0.5 mn/mm 2 TG+Ran 0.5 mn/mm² 2 Hz 6 Hz 10 Hz 500 ms Force Amplitude (mn/mm 2 ) Diastolic tension (mn/mm 2 ) 3 2 1 WT (n=10) TG+Ran (n=11) * TG (n=10)* * RM-ANOVA P<0.05 * 0 0 2 4 6 8 10 Frequency (Hz) 4 3 2 1 TG TG+Ran WT RM-ANOVA P<0.05 0 0 2 4 6 8 10 Frequency (Hz) Sossalla et al., Basic Res Cardiol, 2011 * # * #

rat: Late I Na inhibition improves LVEDP in isolated ischemic hearts in vivo H 2 O 2 LVEDP (mmhg) 75 50 25 Vehicle 5 M Ranolazine 10 M Ranolazine 20 M Ranolazine 0 0 10 20 30 40 Time (min) H 2 O 2 3min Matsumura et al., JPN J Pharmacol, 1998

rabbit: due to an improvement in cellular Na + and Ca 2+ overload [Na + ] i [Ca 2+ ] i 20 700 [Na] i (mm) 16 12 8 4 * [Ca 2+ ] i (nm) 600 500 400 300 200 100 * 0 Baseline H 2 O 2 H 2 O 2 + RAN 0 Baseline H 2 O 2 H 2 O 2 + RAN Song et al., JPET, 2006

Late I Na inhibition diastolic [Ca] & improves LV function during ischemia rat: Diastolic [Ca] LV Function DMSO RAN RAN DMSO Fraser et al., JMCC, 2006

Late I Na inhibition improves LVEDP in a dog: large heart failure animal model Placebo Ranolazine Ranolazine + Enalapril Ranolazine + Metoprolol EF (36%) -9 +2* +5* +8* EDV (60 ml) 9 2* -1* -2 ESV (38ml) 12 0* -3* -5* LVEDP (14 mmhg) +dp/dt (1287 mmhg/s) -dp/dt (1458 mmhg/s) +1-4* -4* -7* -207 163* 270* 121* -270 206* 353* 294 Rastogi et al., Am J Physiol, 2008

Late I Na inhibition reduces LVEDP in vivo in human: patients with ischemic heart disease Hayashida et al., Cardiovasc Drugs & Therapy, 1994

Patients with ACS in MERLIN-TIMI 36 trial human: Morrow et al., JACC, 2010 Is ranolazine more effective than placebo to improve diastolic function in patients with HFpEF?

ClinicalTrials.gov #NCT01163734 EudraCT-No 2009-017168-17 Proof-of-concept study (randomized, doubleblind, placebo-controlled): RALI-DHF (RAnoLazine In Diastolic Heart Failure) 20 patients with symptomatic heart failure (HFpEF) 40 years NYHA II-III, EF 50%, LVEDP 18 mmhg, E/E >15 (or NT-proBNP 220 pg/ml), tau 50 ms ECG, Echo, CPET, NT-proBNP 12 Pat. ranolazine 8 Pat. placebo Acute: heart catheter with hemodynamics before & after i.v. bolus Invasive parameters at rest and paced at 120 beats per min LVEDP, PCWP, CI, MAP, PAP, SVR, PVR, relaxation time, tau, dp/dt, CO Control after 24 h continuous infusion Echo (E/E, E/A, EF), ECG Follow-up after 14 days 2x1 g p.o. Echo (E/E, E/A, EF), ECG, CPET, NT-proBNP

Jacobshagen et al., Clin Cardiol, 2011

Timeline Study start: April 2010 Study completed: January 2011 Jacobshagen et al., Clin Cardiol, 2011

Patient characteristics Placebo Ranolazine Total/Mean Age (years) 73.1±6.4 70.4±7.5 71.5±7.1 Female/male (n) 6/2 10/2 16/4 NYHA II (n) 3 5 8 NYHA III (n) 5 7 12 Hypertension (n) 8 12 20 Diabetes mellitus (n) 4 3 7 Dyslipidemia (n) 5 9 14 Ventricular arrhythmia (n) 0 1 1 Supraventricular arrhythmia (n) 3 2 5 Previous myocardial infarction (n)/ 3 4 7 Angina pectoris (n) Percutaneous coronary 1 3 4 intervention(n) Coronary artery bypass graft (n) 1 2 3 Peripheral vascular disease (n) 0 1 1 Age is presented as mean ± SD

Baseline parameters Placebo Ranolazine normal (n=8) (n=12) EF (%) 59±4 66±7 50 Time constant of relaxation tau (ms) 62±7 59±11 <50 NT-proBNP (pg/ml) 846±1004 666±1059 <220 LVEDP (mmhg) 23±7 21±3 6-12 PCWP (mmhg) 17±8 14±7 6-12 Mean pulmonary artery pressure 29±10 24±8 10-22 (mmhg) E/E 18±6 19±4 5-15 CPET Exercise duration (s) 225±100 398±228 Respiratory exchange ratio (RER) 0.9±0.1 0.8±0.1 >1.1 VE/VCO 2 36±15 35±7 31±5 Data are presented as mean ± SD

Improved LVEDP after ranolazine infusion Individual responses No significant changes in relaxation parameters (e.g. dp/dt, tau) Data are presented as mean ± SEM

Improved PCWP after ranolazine infusion Individual responses Data are presented as mean ± SEM

Improved mpap during pacing (at 120/min) after ranolazine infusion rest Paced at 120/min Data are presented as mean ± SEM

Summary late I Na is found in human heart failure [Na] is associated with diastolic dysfuction Late I Na inhibition improves diastolic function in vitro and in vivo animal models Ranolazine acutely improves diastolic parameters in a small randomized doubleblind, placebo-controlled trial

These promising results justify further clinical evaluations of ranolazine in patients with diastolic dysfunction! Conclusion HFpEF Late I Na Ranolazine NCX Na + overload Ca 2+ overload Mechanical dysfunction Diastolic tension Contractility

Thanks to Göttingen, Germany: Samuel Sossalla Claudius Jacobshagen Rolf Wachter Frank Edelmann Gerd Hasenfuss Gilead, USA: Luiz Belardinelli Ewa Karwatowska-Prokopczuk Beth Layug

Ranolazine reduces LVEDP and CK during cardiac ischemia Langendorff-perfused rabbit heart, 30 min ischemia, 60 min reperfusion; 10 mmol/l ranolazine given 10 min prior ischemia Belardinelli et al., Heart, 2006

Ranolazine improves relaxation in patients with long QT syndrome 3 Moss et al., JCE, 2008